Acquired immunodeficiency syndrome (AIDS) carries a high morbidity rate, with a high incidence of neurological and opthalmogical expressions. Recently, we described the clinical and histopathological features of an AIDS-associated optic neuropathy. The histopathology of these optic nerves resembles progressive diffuse leukoencephalopathy (PDL) characteristic of the brain pathology seen in AIDS. Dramatic morphologic evidence of activated neuroglia and macrophages was seen in association with axons at varying stages of degeneration. We hypothesize that the macrophages associated with degeneration may mediate axon degeneration via the release of various cytokines, particularly tumor necrosis factor (TNF). We are studying the association of TNF with the primary optic neuropathy of AIDS in humans and investigating causality and (to some extent) mechanics, through animal models. The incidence of the primary optic neuropathy of AIDS is now established by psychophysical assessments in AIDS patients and by postmortem optic nerve pathology. We have also succeeded in establishing an animal model of optic nerve axonal degeneration, produced by intravitreal injection of TNF in rabbits. We are continuing to refine and develop this animal model by establishing dose/response curves, following the time course of injury, and looking for different stages of cellular response in the rabbit optic nerve with light microscopy, morphometry, and electron microscopy. TNF levels will be obtained in AIDS patients and controls and correlated with the clinical manifestations of the disease as measured by several ophthalmological and neurological tests. Histopathology and ultrastructure of postmortem AIDS optic nerve will be compared to ur rabbit model. Comparison will also be made to simian AIDS using the monkey model maintained at the California Primate Research Center. This combined clinical/psychophysical, histopathological and immunochemical approach in both human an animal models will contribute to an understanding of the mechanisms of axonal death and may provide a means to test TNF suppressive effects as a potential treatment for AIDS and other conditions.